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Regulation of epithelial-mesenchymal transition and metastasis through phosphorylation of the transcription factor Twist by protein kinase B (PKB/Akt)

English title Regulation of epithelial-mesenchymal transition and metastasis through phosphorylation of the transcription factor Twist by protein kinase B (PKB/Akt)
Applicant Hemmings Brian
Number 130838
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Molecular Biology
Start/End 01.07.2010 - 31.12.2013
Approved amount 468'000.00
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Keywords (9)

Twist1/2; PKB/Akt; epithelial-mesenchymal transition; metastasis; breast cancer; prostate cancer; glioblastoma multiforme; Protein Kinase (PKB/Akt); transcription factor

Lay Summary (English)

Lead
Lay summary
Being one of the most important and versatile protein kinases in human physiology and pathology, the activated PKB (also known as Akt) signaling pathway affects many cellular functions, including metabolism, cell survival, growth, proliferation, cell migration and angiogenesis. Aberrant loss or gain of PKB activation underlies the pathophysiological properties of a variety of diseases, including type-2 diabetes and cancer. Increased PKB expression and activity have been detected in many types of aggressive cancers, such as gastric, breast, prostate, ovarian and brain tumors. Observations of PKB involvement in the regulation of cell migration, epithelial-mesenchymal transition (EMT) and cancer cell invasion has emphasized its importance to tumour progression. Clinical studies of the hyperactivation of PKB in breast cancer patients have shown it to be closely associated with poor prognosis and a higher probability of relapse accompanied by distant metastases. In addition, tumours in the cancer patients that have increased PKB expression tend to be more invasive and metastatic, implying that PKB activation enhances cancer cell migration and invasion. However, the molecular mechanism how the hyperactive PKB signaling pathway regulates cell motility and cancer metastasis is less understood. It was controversially reported that different PKB isoforms play opposite roles in regard to cell migration and invasion. In animal models, it is shown that Akt1 promotes invasiveness of follicular thyroid carcinoma, fibrosarcoma, pancreatic cancer cells et al., which were controversial to other observations.To investigate the molecular link between increased PKB activity and cancer metastasis in attempt to develop therapeutics for druggable targets, we bioinformatically screened protein libraries and identified several proteins that are potentially direct substrates of PKB. Interestingly, some of them have been reported to be critical to regulate cell motility and tumor metastasis in experimental animal models regardless their status of post-translational modification. By using modern molecular and cellular Biochemical methodologies, we are characterizing these candidates to understand their roles during malignant cancer progression in mouse models. We plan to establish that the PI3K/PKB pathway controls EMT and metastasis by its direct substrate phosphorylation. This provides a significant opportunity to inhibit EMT/metastasis by the use of PI3K inhibitors that are currently in clinical tests. Overall our work has the potential to significantly influence late stage cancer patients.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling
Xue Gongda Hemmings Brian (2016), Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling, in Physiological Reviews, 805.
AKT-ions with a TWIST between EMT and MET
Xue Gongda Hemmings Brian (2016), AKT-ions with a TWIST between EMT and MET, in Oncotarget, 62767.
Integrated Akt/PKB signaling in immunomodulation and its potential role in cancer immunotherapy
Xue Gongda Zippelius Alfred Wicki Andreas Mandalà Mario Tang Fengyuan Massi Daniela Hemmings (2015), Integrated Akt/PKB signaling in immunomodulation and its potential role in cancer immunotherapy, in JNCI, 1.
hMOB3 modulates MST1 apoptotic signaling and supports tumor growth in glioblastoma multiform
Tang Fengyuan, Zhuang Lei, Xue Gongda, Hynx Debby, Wang Yuhua, Cron Peter, Hundsrucker Christian, Hergovich Alexander, Frank Stephan, Hemmings Brian, Schmitz Debora (2014), hMOB3 modulates MST1 apoptotic signaling and supports tumor growth in glioblastoma multiform, in Cancer Research, 3779.
Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme
Wang Y, Moncayo G, Morin P, Xue G, Grzmil M, Lino M M, Clément-Schatlo V, Frank S, Merlo A, Hemmings B A (2013), Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme, in Oncogene, 32(7), 872-882.
PKB/Akt-dependent regulation of cell motility
Xue Gongda, Hemmings A. Brian (2013), PKB/Akt-dependent regulation of cell motility, in J Natl Cancer Inst., 105(6), 393-404.
Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGF-β signaling axes.
Xue Gongda, Restuccia David F, Lan Qiang, Hynx Debby, Dirnhofer Stephan, Hess Daniel, Rüegg Curzio, Hemmings Brian A (2012), Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGF-β signaling axes., in Cancer Discovery, 2(3), 248-259.
Phosphorylation of basic helix-loop-helix transcription factor Twist in development and disease.
Xue Gongda, Hemmings Brian A (2012), Phosphorylation of basic helix-loop-helix transcription factor Twist in development and disease., in Biochemical Society transactions, 40(1), 90-3.

Collaboration

Group / person Country
Types of collaboration
University of Turin Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Papa Giovanni XXIII Hospital Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Univesity of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center United States of America (North America)
- Publication
- Research Infrastructure
Ludwig Institute for Cancer Research, University of Lausanne Switzerland (Europe)
- Publication
- Research Infrastructure
University of Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Poster MerTK confers resistance to Vemurafenib in BRAFV600E melanoma 19.10.2013 Boston, MA, United States of America Xue Gongda;
Molecular Targets and Cancer Therapeutics Poster Mer Tyrosine Kinase Confers Vemurafenib-elicited Resistance in Melanoma 19.10.2013 Boston, United States of America Xue Gongda;
Dynamics of Cell Signal Systems - FEBS and Novo Nordic Foundation Poster PI3K/Akt signaling in cancer metastasis 27.09.2012 Oslo, Norway Xue Gongda;
Meeting Membrane dynamics in physiology & disease Poster PI3K/PKB-regulated cancer metastatic potential 05.06.2012 Basel, Switzerland Xue Gongda; Hemmings Brian;
Gordon Research Conference 2012: Cyclic Nucleotide Phosphodiesterases Talk given at a conference Signaling crosstalk between PI3K/Akt and TGFβ/Smad in cancer metastasis 20.05.2012 Ciocco, Italy Xue Gongda;
Fourth Annual European Network of Breast Development and Cancer labs (ENBDC) Talk given at a conference Akt-PKB-Mediated Phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K-Akt and TGF-beta signaling axes 13.04.2012 Weggis, Swizerland, Switzerland Xue Gongda;
Signalling 2011: A Biochemical Society Centenary Celebration Talk given at a conference PKB-mediated Twist1 Phosphorylation Promotes Epithelial-mesenchymal Transition and Cancer Metastasis 08.06.2011 Edinburgh, Great Britain and Northern Ireland Hemmings Brian;
BIT Life Sciences 4th Annual Protein and Peptide Conference Talk given at a conference PKB/Akt-mediated Twist1 phosphorylation on serine 42 promotes epithelial-mesenchymal transition and cancer metastasis 23.03.2011 Beijing, China, China Xue Gongda;
FMI annual meeting Poster PKB/Akt-mediated Twist1 phosphorylation on serine 42 promotes epithelial-mesenchymal transition and cancer metastasis 20.09.2010 Basel, Switzerland, Switzerland Xue Gongda; Hemmings Brian;


Self-organised

Title Date Place
Basel Signaling Symposium “TOR, PI3K and Akt – 20 years on" 11.09.2011 Basel, Switzerland, Switzerland

Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) Inhibiting cell migration in breast cancer German-speaking Switzerland 2012
Media relations: print media, online media Schweizer Forscher finden Ansatz gegen aggressiven Brustkrebs SchweizerischeDepeschenagentur German-speaking Switzerland 2012

Patents

Title Date Number Inventor Owner
Phosphorylated Twist1 and cancer metastasis 10.09.2010 PCT/EP2011/065615

Associated projects

Number Title Start Funding scheme
133860 High Content and High Throughput Microscopy to Decipher Signaling Networks 01.12.2010 R'EQUIP
138287 Investigating the in vivo roles of mammalian NDR kinases in development and colon cancer 01.12.2011 Project funding (Div. I-III)

Abstract

The basic aim of this proposal is to target the PKB signalling pathway in epithelial-mesenchymal transition (EMT) and metastasis.A growing body of the data indicates that PKB signalling pathway plays vital roles in invasive tumor progression. However, the mechanism of the regulation is unclear. In addition to cancer cell line-based studies, we will mainly use animal models of three invasive cancers (breast, prostate and skin cancers) to investigate the PKB singalling-dependent regulation of EMT and metastasis through Twist1 phosphorylation in order to look for more specific therapeutic targets for clinical treatments.
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